Adenoviruses (Ads) are promising vectors for therapeutic interventions in humans (Thomas et al., 2003). Despite significant knowledge regarding the biology of Ad interactions with cells in vitro, the molecular mechanisms governing in vivo Ad infectivity and bio-distribution remain poorly understood (Baker, 2007; Khare et al.). This poses significant risks for their intravascular administration and represents the major hindrance for safe, selective, and efficient Ad targeting to specific cell and tissue types in vivo.
Pharmacokinetic studies of Ad vectors after intravascular delivery demonstrate that the majority of an administered virus dose is rapidly sequestered from the circulation by the liver (Alemany and Curiel, 2001; Di Paolo et al., 2009b; Khare et al., 2011a). Through comprehensive in vivo analyses, it was found that the general molecular mechanisms that mediate Ad sequestration by liver tissue operate in a redundant and synergistic manner (Di Paolo et al., 2009b). Specifically, it is currently believed that Ad particles are distributed in liver tissue amongst three distinct cellular compartments, namely i) parenchymal liver cells—hepatocytes, ii) hepatic residential macrophages, Kupffer cells, and iii) hepatic sinusoid endothelial cells. Importantly, the ablation of Ad interaction with only one of these cellular compartments cannot prevent virus trapping the liver and results in compensatory re-distribution of the virus among two remaining cellular compartments, functionally ensuring the quantitative removal of the virus from the blood (Di Paolo et al., 2009b). Despite of this general understanding of the redundancy of mechanisms that may operate to remove Ad particles from the blood and trap them in the liver after intravascular virus administration, the exact molecular mechanisms guiding Ad interactions with liver cells in vivo remain controversial (Baker et al., 2013). This controversy and the lack of understanding of mechanisms that operate to trap Ad particles in the liver is ultimately manifested in the fact that to date, no Ad vector configurations were reported that would, based on purely genetic (and not chemical) modification of Ad capsid proteins, allow for generation of Ads, which would escape being sequestered in the liver at a physical particle level after intravascular virus delivery. Ad trapping in the liver is deleterious for gene therapy and cancer therapy applications, since Ad particles sequestered in the liver become destroyed, necessitating high virus doses to achieve transduction of any extra-hepatic cells. High Ad doses injected intravenously activate severe systemic inflammatory response that can be fatal (Brunetti-Pierri et al., 2004; Raper et al., 2003; Raper et al., 2002). What is needed are new Ad vectors that avoid liver sequestration and activation of inflammation and methods of accomplishing the same.